Recombinant macromolecules are of considerable interest to pharmaceutical and biotechnological research and include both nucleic acids (ribo- and deoxyribonucleic acids) and proteins. Of these, recombinant proteins receive the most attention due to their diversity and numerous applications. Certain aspects of pharmaceutical and biotechnological research are dependent upon the production of recombinant macromolecules. Such recombinant macromolecules are produced in a variety of host cells including, but not limited to, bacterial cells (e.g., Escherichia coli), yeast cells, insect cells, and mammalian cells. In many instances, the recombinant macromolecule is produced in a heterologous host cell, i.e., a host cell that is different from the macromolecule's native source. For example, the biotechnology drug human growth hormone, which is a secreted protein from the human pituitary gland, is produced recombinantly in the bacterium Escherichia coli (E. coli). Such heterologous host cell systems do not always successfully produce the desired recombinant macromolecule. Often times the desired protein can be misfolded in the heterologous host cell (i.e., it does not have its native structure and is therefore nonfunctional), or expressed in a form that is insoluble, toxic, aggregated, or degraded. Often the recombinant macromolecule is simply produced in insufficient quantities in the heterologous host cell. Modified recombinant proteins or recombinant fusion proteins may also pose production challenges, even in homologous host cell systems, due to their unnatural compositions.
A common approach to address the above-noted challenges of recombinant macromolecule production is the use of alternative host cell systems. However, certain macromolecular production problems, such as misfolded proteins, are addressed post production in the host cell system, which can be labor intensive as well as not being effective for all proteins. In addition, addressing these issues is generally a protein specific process, resulting in low throughput. Another method to address certain macromolecular production problems involves the use of cell-free protein expression systems. A practical limitation of these systems is that they are not scalable. The protein production limit of cell-free expression systems is generally 50 milligrams or less, and often the production limit is just a few milligrams. In addition, storage of the cell extracts and cell lysates leads to a diminution in their capacity to produce protein. These systems also have no meaningful capacity to produce significant amounts of nucleic acid and therefore require a second system to provide a supply of the requisite DNA template.